The σ1 Receptor Engages the Redox-Regulated HINT1 Protein to Bring Opioid Analgesia Under NMDA Receptor Negative Control

Abstract

Aims: The in vivo pharmacology of the sigma 1 receptor (σ1R) is certainly complex; however, σ1R antagonists are of therapeutic interest, because they enhance mu-opioid receptor (MOR)-mediated antinociception and reduce neuropathic pain. Thus, we investigated whether the σ1R is involved in the negative control that glutamate N-methyl-d-aspartate acid receptors (NMDARs) exert on opioid antinociception. Results: The MOR C terminus carries the histidine triad nucleotide-binding protein 1 (HINT1) coupled to the regulator of G-protein signaling RGSZ2-neural nitric oxide synthase assembly. Activated MORs stimulate the production of nitric oxide (NO), and the redox zinc switch RGSZ2 converts this signal into free zinc ions that are required to recruit the redox sensor PKCγ to HINT1 proteins. Then, PKCγ impairs HINT1-RGSZ2 association and enables σ1R-NR1 interaction with MOR-HINT1 complexes to restrain opioid signaling. The inhibition of NOS or the absence of σ1Rs prevents HINT1-PKCγ interaction, and MOR-NMDAR cross-regulation fails. The σ1R antagonists transitorily remove the binding of σ1Rs to NR1 subunits, facilitate the entrance of negative regulators of NMDARs, likely Ca2+-CaM, and prevent NR1 interaction with HINT1, thereby impairing the negative feedback of glutamate on opioid analgesia. Innovation: A redox-regulated process situates MOR signaling under NMDAR control, and in this context, the σ1R binds to the cytosolic C terminal region of the NMDAR NR1 subunit. Conclusion: The σ1R antagonists enhance opioid analgesia in naïve mice by releasing MORs from the negative influence of NMDARs, and they also reset antinociception in morphine tolerant animals. Moreover, σ1R antagonists alleviate neuropathic pain, probably by driving the inhibition of up-regulated NMDARs. Antioxid. Redox Signal. 22, 799–818.

A Review of the Human Sigma-1 Receptor Structure

“…It is possible that the interface for protein-protein interactions is only accessible in the monomeric form [32,62,63], however, the surface-exposed helices A and B are attractive potential sites of interaction based on the trimeric structures. Residues 61-65 in helix B form a putative SUMO interaction site, and peptide interference assays are consistent with the binding of the GluR1 cytoplasmic tail near this region [57]. Furthermore, the helices lie against the large β-sheet enclosing the ligand binding site, and helix B contacts L106, which has been proposed to be involved in discriminating between agonist and antagonist [31].…”

“…Thus, the S1R membrane topology makes it difficult to rationalize how the receptor could interact with proteins both in the cytoplasm and in the ER lumen. Interactions with several proteins or regions of protein that are found exclusively in the cytoplasm or the nucleus, including the C-terminus of the GluR1 subunit of the ionotropic glutamate receptor [57], STIM1 [58], and emerin [12], are consistent with S1R being a Type I membrane protein with a cytosolic C-terminus. However, an interaction at the C-terminus of S1R with BiP has been shown in cell extracts [2] and in vitro [25].…”

Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice

“…Naloxone methiodide does not bind to sigma-1 receptors (10), and conversely, the sigma-1 antagonists BD-1063 and S1RA do not bind to opioid receptors (9,17). However, sigma-1 receptors can form macromolecular complexes with opioid receptors to produce tonic inhibition of receptor functioning (12,13). Sigma-1 antagonism is well known to increase opioid agonistinduced signaling, resulting in the potentiation of opioid analgesia by sigma-1 antagonists (12,13).…”

“…However, sigma-1 receptors can form macromolecular complexes with opioid receptors to produce tonic inhibition of receptor functioning (12,13). Sigma-1 antagonism is well known to increase opioid agonistinduced signaling, resulting in the potentiation of opioid analgesia by sigma-1 antagonists (12,13). Therefore, a possible explanation for the sensitivity of sigma-1-mediated antihyperalgesic effects to opioid antagonism is that naloxone methiodide antagonizes peripheral opioid receptors, thereby impeding the action of endogenous opioid agonists produced at the site of inflammation (whose action is maximized by sigma-1 antagonism), resulting in noncompetitive inhibition of the antihyperalgesic effects induced by sigma-1 antagonism.…”

“…Moreover, these receptors in the dorsal root ganglion are selectively located in sensory neurons and not in glial cells (11). It is now known that sigma-1 receptors can form a macromolecular complex with opioid receptors, tonically inhibiting receptor functioning, and that sigma-1 antagonism can protect opioid receptors from the tonic inhibitory effects of sigma-1 receptors, thus enhancing opioid analgesia (12,13). However, although the ability of sigma-1 antagonism to potentiate the analgesic effects of opioid drugs is clear, the physiological and pathophysiological roles of sigma-1 receptors in opioid modulation remain unknown.…”